Incidence of Hip and Subtrochanteric/Femoral Shaft Fractures in Postmenopausal Women With Osteoporosis in the Phase 3 Long-Term Odanacatib Fracture Trial

Abstract

We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged ≥65 years with a bone mineral density (BMD) T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a radiographic vertebral fracture and T-scores ≤−1.5 at the TH or FN were randomized (1:1) to receive ODN 50 mg/week or placebo. All patients received vitamin D 3 (5600 IU/week) and calcium (total 1200 mg/d); the analysis included 16,071 women. Rates of all adjudicated low-energy femoral fractures were 0.38 versus 0.58/100 patient-years for ODN and placebo, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI] 0.51-0.82; nominal p < .001), and for low-energy hip fractures were 0.29 versus 0.56/100 patient-years, respectively (HR = 0.52; 95% CI 0.40-0.67; p < .001). The cumulative incidence of combined hip and ST/FS or hip fractures alone in the ODN group was consistently lower than in the placebo group (1.93% versus 3.11% for combined fractures and 1.53% versus 3.03% for hip fractures at 5 years, respectively). However, low-energy ST/FS fractures were more frequent in ODN-treated women than in placebo-treated women (24 versus 6, respectively). Among these, 12 fractures were adjudicated as AFF in 10 patients treated with ODN (0.03/100 patient-years) compared with none in the 6 placebotreated women (estimated difference 0.03; 95% CI 0.02-0.06). These results provide insight into possible pathogeneses of AFF, suggesting that the current criteria for diagnosing these fractures may need to be reconsidered.

Twelve Months of Denosumab and/or Alendronate Is Associated With Improved Bone Fatigue Life, Microarchitecture, and Density in Ovariectomized Cynomolgus Monkeys

“…In light of the current results, it may be noteworthy that a recent clinical study ( 63 ) found higher AFF risk in individuals treated with the cathepsin K inhibitor odanacatib, a drug that causes lesser inhibition of bone resorption than DMAb. This suggests that alternative hypotheses for the etiological link between antiresorptive use and AFF beyond the effects of osteoclast inhibition may be warranted.…”

The incidence, prevalence, and health burden of hip fractures in China: Data from the global burden of disease study 2019

“…It is not possible to determine the proportion of fragile hip fractures caused by low trauma causes in patients with osteoporosis. However, hip fractures in people over 60 years of age are mainly caused by low-energy trauma, and the incidence is higher in women than that in men ( Papapoulos et al, 2021 ), which may be explained by the high incidence of postmenopausal osteoporosis in women. Besides, our study revealed that the incidence and disease burden of hip fractures are mainly seen in the elderly, suggesting that a great proportion of hip fractures estimated for China are fragile fractures.…”

Incidence of Atypical Femoral Fractures in Patients on Osteoporosis Therapy—A Registry‐Based Cohort Study

“…(27) AFFs were also reported in patients taking romosozumab (30) or odanacitinib. (31,32) Although all of these drugs act at least in part by inhibiting bone resorption, the sequential use of first bisphosphonates, followed by highly active antiresorptive agents may lead to earlier AFF onset than with long-term BP monotherapy. In this study, one patient developed an AFF under denosumab after receiving antiresorptive therapy for a total of <5 years.…”